ArticleProceedings of the National Academy of Sciences of the United States of America2018
Inferring the shape of global epistasis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 169 papers.
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169 citing papers in PubMed.
- Article
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- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- Inference of fitness landscapes with heterogeneous patterns of epistasis across sites.bioRxiv : the preprint server for biology · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Machine Learning-Driven Simulations of the SARS-CoV-2 Fitness Landscape from Deep Mutational Scanning Experiments.Journal of chemical information and modeling · 2026Article
- Evolutionary rate correlations reveal long-term co-evolutionary interactions inbioRxiv : the preprint server for biology · 2026Article
- GaugeFixer: overcoming parameter non-identifiability in models of sequence-function relationships.bioRxiv : the preprint server for biology · 2026Article
- Mount Fuji's stubby peak: the genotypic density of additive landscapes near maximal fitness.bioRxiv : the preprint server for biology · 2026Article
- A simple model captures key characteristics of biological non-deterministic genotype-phenotype maps.PLoS computational biology · 2026Article
- On learning functions over biological sequence space: relating Gaussian process priors, regularization, and gauge fixing.Journal of mathematical biology · 2026Article
- PoolParty: streamlined design of DNA sequence libraries in Python.bioRxiv : the preprint server for biology · 2026Article
- Determinants of metal import and specificity in a bacterial transporter.bioRxiv : the preprint server for biology · 2026Article
- Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.bioRxiv : the preprint server for biology · 2026Article
- Origins and breadth of pairwise epistasis in an α-helix of β-lactamase TEM-1.Nature communications · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Predicting viral sensitivity to antibodies using genetic sequences and antibody similarities.PLoS computational biology · 2026Article
109 more citing papers are in PubMed but not listed here.
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3 authors.
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Abstract
Genotype-phenotype relationships are notoriously complicated. Idiosyncratic interactions between specific combinations of mutations occur and are difficult to predict. Yet it is increasingly clear that many interactions can be understood in terms of global epistasis. That is, mutations may act additively on some underlying, unobserved trait, and this trait is then transformed via a nonlinear function to the observed phenotype as a result of subsequent biophysical and cellular processes. Here we infer the shape of such global epistasis in three proteins, based on published high-throughput mutagenesis data. To do so, we develop a maximum-likelihood inference procedure using a flexible family of monotonic nonlinear functions spanned by an I-spline basis. Our analysis uncovers dramatic nonlinearities in all three proteins; in some proteins a model with global epistasis accounts for virtually all of the measured variation, whereas in others we find substantial local epistasis as well. This method allows us to test hypotheses about the form of global epistasis and to distinguish variance components attributable to global epistasis, local epistasis, and measurement error.
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